IP Library › Granted Patent US 12,703,761
Granted Patent B2
US 12,703,761 · App. 19/352,786 · Granted Aug 11, 2026

Anti-HER2 antibodies and methods of use thereof

Inventors: Abira Bandyopadhyay (Pleasanton, CA); Allisa Jayne Clemens (San Jose, CA); Do Jin Kim (Albany, NY); Michelle E. Pizzo (Pacifica, CA); Lu Shan (Belmont, CA); Richard Théolis, Jr. (Santa Cruz, CA); Raymond Ka Hang Tong (South San Francisco, CA)
Assignee: Denali Therapeutics Inc.
C07K16/32A61K35/00A61K45/06A61K2039/505C07K2317/31C07K2317/526C07K2317/565C07K2317/71C07K2317/72C07K2317/732C07K2317/92
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Quick Facts
Patent No.
US 12,703,761
App. No.
19/352,786
Filed
Oct 8, 2025
Granted
Aug 11, 2026
Kind
B2
Art Unit
1646
USPC
424/136.1
Abstract

In one aspect, antibodies that bind to subdomain II of human HER2 are provided. In another aspect, antibodies comprising a light chain polypeptide that pairs with both a heavy chain polypeptide for binding to subdomain II of human HER2 and a heavy chain polypeptide for binding to subdomain IV of human HER2 are provided. In a further aspect, antibodies that bind to both subdomain II and subdomain IV of human HER2 comprising a common light chain polypeptide are provided. Methods of treating a cancer or treating brain metastasis of a cancer using these antibodies are also provided.

Claims (53)

1 . An isolated antibody comprising:

(a) a first heavy chain comprising a first heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:16, a first heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:17, and a first heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 18;

(b) a second heavy chain comprises a second heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:4; a second heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:6, and a second heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:8;

(c) first and second light chains, wherein the first and second light chains each comprise a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:11, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:12, and a light chain CDR 3 comprising the amino acid sequence of SEQ ID NO:14;

(d) a first Fc polypeptide comprising:

(i) Glu at position 380; Tyr at position 384; Thr at position 386; Glu at position 387; Trp at position 388; Val at position 389; Asn at position 390; Thr at position 413; Glu or Ser at position 415; Glu at position 416; and Phe at position 421, according to EU numbering; and

(ii) an Ala at position 234 and Ala at position 235, according to EU numbering; and

(e) a second Fc polypeptide does not contain a TfR-binding site or any modifications that reduce effector function.

2 . The isolated antibody of claim 1 , wherein the first Fc polypeptide further comprises a P329G or a P329S substitution, according to EU numbering.

3 . The isolated antibody of claim 2 , wherein the second Fc polypeptide comprises: a Leu at position 234, a Leu at position 235, and a Pro at position 329, according to EU numbering.

4 . The isolated antibody of claim 3 , wherein:

(a) the first heavy chain comprises the first Fc polypeptide and the second heavy chain comprises the second Fc polypeptide; or

(b) the first heavy chain comprises the second Fc polypeptide and the second heavy chain comprises the first Fc polypeptide.

5 . The isolated antibody of claim 4 , wherein an antibody hinge region or a portion thereof is linked to the N-terminus of the first Fc polypeptide and/or the second Fc polypeptide.

6 . The isolated antibody of claim 5 , wherein the first Fc polypeptide and/or the second Fc polypeptide independently comprises a S239D and/or an I332E substitution, according to EU numbering.

7 . The isolated antibody of claim 6 , wherein:

(a) the first Fc polypeptide comprises a S239D substitution;

(b) the second Fc polypeptide comprises a S239D substitution;

(c) the first Fc polypeptide comprises a S239D substitution and the second Fc polypeptide comprises a S239D substitution;

(d) the first Fc polypeptide comprises an I332E substitution;

(e) the second Fc polypeptide comprises an I332E substitution;

(f) the first Fc polypeptide comprises an I332E substitution and the second Fc polypeptide comprises an I332E substitution;

(g) the first Fc polypeptide comprises a S239D substitution and the second Fc polypeptide comprises an I332E substitution;

(h) the first Fc polypeptide comprises an I332E substitution and the second Fc polypeptide comprises a S239D substitution;

(i) the first Fc polypeptide comprises a S239D and an I332E substitution;

(j) the second Fc polypeptide comprises a S239D and an I332E substitution;

(k) the first Fc polypeptide comprises a S239D and an I332E substitution and the second Fc polypeptide comprises a S239D substitution;

(l) the first Fc polypeptide comprises a S239D and an I332E substitution and the second Fc polypeptide comprises an I332E substitution;

(m) the first Fc polypeptide comprises a S239D substitution and the second Fc polypeptide comprises a S239D and an I332E substitution;

(n) the first Fc polypeptide comprises an I332E substitution and the second Fc polypeptide comprises a S239D and an I332E substitution; or

(o) the first Fc polypeptide comprises a S239D and an I332E substitution and the second Fc polypeptide comprises a S239D and an I332E substitution.

8 . The isolated antibody of claim 7 , wherein the first Fc polypeptide and the second Fc polypeptide each comprises modifications that promote heterodimerization.

9 . The isolated antibody of claim 8 , wherein:

(a) the first Fc polypeptide comprises a T366W substitution and the second Fc polypeptide comprises a T366S substitution;

(b) the second Fc polypeptide comprises a T366W substitution and the first Fc polypeptide comprises a T366S substitution;

(c) the first Fc polypeptide comprises a T366W substitution and the second Fc polypeptide comprises T366S, L368A, and Y407V; or

(d) the second Fc polypeptide comprises a T366W substitution and the first Fc polypeptide comprises T366S, L368A, and Y407V substitutions,

wherein the positions are according to EU numbering.

10 . The isolated antibody of claim 9 , wherein the first Fc polypeptide comprises a Glu at position 415.

11 . The isolated antibody of claim 9 , wherein the first Fc polypeptide comprises a Ser at position 415.

12 . An anti-HER2 antibody comprising:

(a) a first heavy chain comprising (i) a first heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:16, a first heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:17, and a first heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:18; (ii) a hinge region comprising SEQ ID NO:96; and (iii) a first Fc polypeptide comprising: an Ala at position 234, an Ala at position 235, an Asp at position 239, a Ser at position 329, a Trp at position 366, a Glu at position 380, a Tyr at position 384, a Thr at position 386, a Glu at position 387, a Trp at position 388, a Val at position 389, a Gln at position 390, a Thr at position 413, a Glu or Ser at position 415, a Glu at position 416, a Phe at position 421, wherein the positions are according to EU numbering;

(b) (i) a second heavy chain comprises a second heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:4; a second heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:6, and a second heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:8; (ii) a hinge region comprising SEQ ID NO:96; and (iii) a second Fc polypeptide comprising: a Glu at position 332, a Ser at position 366, an Ala at position 368, and a Val at position 407, wherein the positions are according to EU numbering; and

(c) first and second light chains, wherein the first and second light chains each comprise a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:11, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:12, and a light chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 14.

13 . A pharmaceutical composition comprising the anti-HER2 antibody of claim 12 and a pharmaceutically acceptable carrier and/or excipient.

14 . Isolated polynucleotides or one or more expression vectors comprising nucleotide sequences encoding polypeptides that comprise the anti-HER2 antibody of claim 12 .

15 . One or more host cells comprising the nucleotide sequences of claim 14 .

16 . A method of making an anti-HER2 antibody comprising culturing the one or more host cells of claim 13 under conditions appropriate for expressing the nucleic acid sequences encoding polypeptides that comprise the anti-HER2 antibody, and isolating the polypeptides that comprise the anti-HER2 antibody expressed by the one or more host cells, wherein the isolate polypeptide are used to make the anti-HER2 antibody.

17 . A method of treating a HER2-positive cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 13 .

18 . The method of claim 17 , wherein the cancer is: a breast cancer, an ovarian cancer, a bladder cancer, a salivary gland cancer, an endometrial cancer, a pancreatic cancer, a non-small-cell lung cancer, a gastric adenocarcinoma, or a gastroesophageal junction adenocarcinoma.

19 . The method of claim 18 , wherein the cancer is: a metastatic cancer or a brain metastasis of the cancer.

20 . The method of claim 18 , wherein the isolated antibody is administered in combination with a chemotherapy or radiation therapy.

21 . The method of claim 19 , wherein the isolated antibody is administered in combination with a chemotherapy or radiation therapy.